Diabetic nephropathy is one of the most important complications of diabetes and is the leading cause of renal replacement therapy in the US.¹ According to the American Diabetes Association guidelines,² treatment for individuals with non-dialysis-dependent diabetic nephropathy can be summarized as: 1) optimal glycemic control, 2) dietary protein restriction (0.8 g/kg of body weight/day), and 3) the use of angiotensin-converting-enzyme inhibitor or angiotensin receptor blockers. Historically, the UK Prospective Diabetes Study showed that intensive glucose control (average achieved hemoglobin [Hb] A1c, 7.0%) reduced the risk of microvascular endpoints including kidney failure by 25% compared to the conventional treatment (achieved HbA1c of 7.9%).³

In the last few years, several new diabetic medications have been tested for their renoprotective effect when added to standard care. Two trials of dipeptidyl peptidase-4 (DPP-4) inhibitors failed to show this benefit.^4,5 On the other hand, liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduced the risk of the composite renal outcome, including the need for continuous renal replacement therapy.⁶ However, the requirement of subcutaneous injection is a drawback.

In this context, a recent secondary analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial comparing empagliflozin,^7,8 a sodium–glucose cotransporter 2 (SGLT-2) inhibitor, vs. placebo may provide new insights into the management of diabetic nephropathy. In this trial, 7,020 patients with type 2 diabetes mellitus (T2DM) (mean age 63 years; HbA1c 8.1%) and established cardiovascular disease (CVD) were randomized to either receive placebo or empagliflozin (at a dose of 10 mg or 25 mg). Persons with an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m² were excluded. Over a median follow-up of 3.1 years, the trial assessed a composite kidney outcome comprised of progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, and death from renal disease.

In the main analysis comparing the pooled empagliflozin doses to placebo, empagliflozin was associated with a 39% reduction in the composite kidney outcome (525 of 4124 patients [12.7%] in the empagliflozin group vs. 388 of 2061 [18.8%] in the placebo group [HR, 0.61; 95% CI 0.53, 0.70]). The results were consistent for each individual component of doubling of the serum creatinine (70 of 4645 patients [1.5%] in the empagliflozin group vs. in 60 of 2323 [2.6%] in the placebo group), the need of renal-replacement therapy (13 of 4687 patients [0.3%] in the empagliflozin group vs. 14 of 2333 patients [0.6%] in the placebo group), and progression to macroalbuminuria (459 of 4091 patients [11.2%] in the empagliflozin group and in 330 of 2033 [16.2%] in the placebo group). Meanwhile, empagliflozin did not reduce the risk of incident albuminuria, defined as newly identified urinary albumin-to-creatinine ratio ≥ 30 mg/g, among those without albuminuria at randomization (1430 of 2779 [51.5%] in the empagliflozin group and 703 of 1374 [51.2%] in the placebo group; [HR, 0.95; 95%CI, 0.87, 1.04]). The results were consistent regardless of baseline kidney status and demographic characteristics. Of interest, there was no difference in renoprotective effects between two different doses of empagliflozin, 10 mg vs. 25mg.

There may be several plausible explanations behind the renoprotective effect seen in the EMPA-REG OUTCOME trial. First, empagliflozin substantially improved glycemic control. After 12 weeks of randomization, the mean differences in the HbA1c comparing to the placebo group were -0.54% (95% CI, -0.58, -0.49) in the 10 mg group and -0.60% (95% CI, -0.64, -0.55) in the 25 mg group. Second, empagliflozin resulted in better profiles in terms of kidney risk factors such as decreased body weight and reduced blood pressure.⁷ Third, a reduced risk of cardiovascular events in the empagliflozin group may also play a role,⁸ given the tight link between CVD and kidney disease (socalled cardiorenal syndrome). Finally, there may be unique renoprotective effects of SGLT-2 inhibitors. In animal models, empagliflozin prevented glomerular hyperfiltration by lowering the intraglomerular pressure and reduced expression of fibrosis markers in tubulointerstitium.^9,10 In addition, SGLT-2 inhibitors lower blood glucose by inhibiting glucose absorption in the kidney primarily at the proximal tubule,¹¹ which may result in lower renal interstitial glucose levels and thus may prevent local proximal tubular glucotoxicity.

Although this secondary analysis provides important clinical implications, several caveats should also be acknowledged. The trial included only T2DM individuals with established CVD. Thus, whether the results can be generalizable to those without CVD is yet to be determined. In addition, the follow-up period was relatively short compared to the natural history of diabetic nephropathy,¹² resulting in a small number of clinically relevant kidney events. It would be valuable if we can see long-term kidney effects with an extended follow-up from the trial in the future. We also need to keep in mind that the original sample size calculation was based on the CVD event rate but not for kidney outcomes. With the lack of a clear dose dependent effect, if the renoprotecitve effect is confirmed in other trials, an optimal dose may need to be explored. Also, the potential for adverse effects of SGLT-2 inhibitors, such as risk of ketoacidosis and bone fracture,^13,14 is another concern. Finally, as is often the case with a newly developed drug, empagliflozin is costly relative to the majority of other antidiabetic medications; the average wholesale price for a 30-day supply is reported as $411.¹⁵

Nonetheless, this secondary analysis from the EMPA-REG OUTCOME trial marked an important milestone demonstrating initial evidence of a potential benefit of SGLT-2 inhibitors on kidney outcomes. Since therapeutic options for preventing the progression of diabetic nephropathy are limited, replication of their results in other clinical and demographic settings would be crucial. To date, three SGLT-2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) have been approved for use in adults with T2DM by the U.S. Food and Drug Administration.¹⁶ Currently two clinical trials of canagliflozin, the CANVAS-R (A Study of the Effects of Canagliflozin [JNJ-28431754] on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus) trial and the CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetec Nephropathy) trial, focusing on the effect on kidney events as the primary outcome are ongoing. The results of these trials will further provide insights regarding how sweet the SGLT-2 inhibitors would be for the kidney in patients with diabetes.

References

1. Saran R, Li Y, Robinson B, et al. US Renal Data System 2014 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis 2015;66:S1-305.
2. American Diabetes Association. 9 microvascular complications and foot care. Diabetes Care 2016;39:S72-80.
3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sylphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352;837-53.
4. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2013;369:1317-26.
5. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.
6. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
7. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-34.
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
9. Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 2014;306:F194-204.
10. Gallo LA, Ward MS, Fotheringham AK, et al. Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice. Sci Rep 2016;6:26428.
11. Scheen AJ. Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol 2014;10:647-63.
12. Adler AI, Stevens RJ, Manley Se, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63:225-32.
13. Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab 2015;100:2849-52.
14. Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 2015;3:8-10.
15. Ndefo UA, Anidiobi NO, Basheer E, Eaton AT. Empagliflozin(Jardiance): a novel SGLT2 inhibitor for the treatment of type-2 diabetes. P T 2015;40:364-8.
16. Murray CJ, Atkinson C, Bhalla K, et al. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA 2013;310:591-608.

Keywords: Albumins, Albuminuria, Angiotensin Receptor Antagonists, Benzhydryl Compounds, Blood Glucose, Blood Pressure, Body Weight, Cardio-Renal Syndrome, Creatinine, Demography, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Dipeptidyl-Peptidase IV Inhibitors, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Fractures, Bone, Glomerular Filtration Rate, Glucagon-Like Peptide 1, Glucose, Glucosides, Glycated Hemoglobin A, Hypoglycemic Agents, Ketosis, Prospective Studies, Renal Dialysis, Renal Replacement Therapy, Risk Factors, Metabolic Syndrome

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